Terpenes Glycosides2

Glycosides

are compounds containing a carbohydrate and a noncarbohydrate residue in the same molecule. The carbohydrate residue is attached by an acetal linkage at carbon atom 1 to a noncarbohydrate residue or AGLYCONE. The nonsugar component is known as the AGLYCONE. The sugar component is called the GLYCONE. If the carbohydrate portion is glucose, the resulting compound is a GLUCOSIDE. An example is the methyl glucoside formed when a solution of glucose in boiling methyl alcohol is treated with 0.5% HCl as a catalyst.

The aglycone may be methyl alcohol, glycerol, a sterol, a phenol, etc.

     CLASSIFICATION OF GLYCOSIDES

When the chemical nature of the aglycone group is used as the basis of systematization, the classification is:         

Squalene, a triterpene, is a precursor of steroids

• Many hormones are steroids

Steroids

Methyl groups at C-10 and C-13 are called angular methyl groups

The B, C, and D rings are trans fused

Thoseon the opposite side of the plane of the ring system are -substituents

Substituents on the same side of the steroid ring systemas the angular methyl groups are -substituents

The A and B rings are also trans fused in most naturallyoccurring steroids

Biosynthesis of Cholesterol

Synthetic Steroids

STEROIDS Steroids form an important group of compounds based on the fundamental saturated tetracyclic hydrocarbon : 1,2-cyclopentano-perhydro-phenanthrene.

                                                                This nucleus, partially or completely hydrogenated, is generally substituted by methyl groups at C10 and C13. A chemical group (ketone, hydroxyl...) or an alkyl side-chain may also be present at C17. Steroids may possess a nucleus derived from sterane by one or more C-C bond scissions or ring expansions or contractions.

As natural steroids are derived from squalene by cyclization, unsaturation and substitution, they may be considered as modified triterpenes.

FREE STEROLS

Sterols form an important group among the steroids. Unsaturated steroids with most of the skeleton of cholestane containing a 3β-hydroxyl group and an aliphatic side chain of 8 or more carbon atoms attached to position 17 form the group of sterols. 

In animals, another sterol, lanosterol (C30 compound) is found as a major constituent of the unsaponifiable portion of wool fat (lanoline) and was shown to be an intermediate in the biosynthesis of cholesterol. Animal tissues contain in addition to cholesterol small amounts of 7-dehydrocholesterol.

In the tissues of vertebrates, the main sterol is the C27 alcohol cholesterol

(Greek, chole, bile), particularly abundant in adrenals (10%, w/w), nervous

tissues (2%,w/w), liver (0.2%,w/w) and gall stones, its fundamental carbon

structure being a cyclopentano-perhydro-phenanthrene ring (also called sterane).

It was the first isolated sterol around 1770 by Poulletier de La Salle from gall

stones. In 1815, it was isolated from the unsaponifiable fraction of animal fats and

named cholesterine (Greek, khole, bile and stereos, solid). The correct formula

(C27H46O) was proposed in 1888 by F. Reinitzer but structural studies from

1900 to 1932, mainly by H.O. Wieland "on the constitution of the bile acids and

related substances" (Nobel Prize Chemistry 1927) and by A.O.R. Windaus on

"the constitution of sterols and their connection with the vitamins" (Nobel Prize

Chemistry 1928), led to the exact steric representation of cholesterol.

In 1936, Callow and Young designated as steroids all compounds chemically

related to cholesterol.

In higher plants, the first sterols were isolated by Hesse (1878) from the Calabar beans

(Phytostigma venenosum) which coined the term "phytosterine".

This substance was later named stigmasterol (Windaus and Hault, 1906) from the plant

genus.

The denomination "phytosterol" was proposed in 1897 for all sterols of vegetal origin.

Chemically, these sterols have the same basic structure as cholesterol but differences

arise from the lateral chain on carbon 17. Most phytosterols are compounds having 28 to

30 carbon atoms and one or two carbon-carbon double bonds, typically one in the sterol

nucleus and sometimes a second in the alkyl side chain. 

All phytosterols were shown to derive from cycloartenol, direct product of the cyclization

of squalene in plants.                                                                            

More than 200 different types of phytosterols have been reported in plant species. Representatives of these sterols are campesterol, stigmasterol and -sitosterol which is present in all plant lipids and is used for steroid synthesis. An important C28 sterol from the fungus Claviceps purpurea (ergot) is ergosterol (mycosterol).

As ergosterol is a cell membrane component largely restricted to fungi, its amount in environmental matrices may be used as an index molecule for these micro-organisms in a living biomass.

STEROL ESTERS

In animal tissues, especially in the liver, adrenals and plasma lipids, cholesterol is esterified by a variety of fatty acids and most frequently by essential fatty acids, thus forming cholesterol

esters. Thus, the esterification of cholesterol with arachidonic acid gives cholesteryl arachidonate.

Sterol esters are important but highly variable components of the yeast cell with values ranging from traces to 50% of the total lipids.

The esterification of free cholesterol within intestinal cells allows the cholesterol to be stored as a neutral lipid in cytosolic droplets and in the packing of cholesterol into lipoprotein particles for

export via the plasma to liver cells.  

STERYL GLYCOSIDES

This family consists of one carbohydrate unit linked to the hydroxyl group of one sterol molecule. 

The sterol moiety was determined to be composed of various sterols: campesterol, stigmasterol,

sitosterol, brassicasterol and dihydrositosterol. The sugar moiety is composed of glucose, xylose

and even arabinose.

In bacteria, Helicobacter was shown to be particularly rich in cholesterol glucosides (up to 33% of

total lipids), thus suggesting that these molecules may be important chemotaxonomic markers for

these species. 

It was shown that sterol glucosides participate in the synthesis of cellulose.

SAPONIN GLYCOSIDES Saponin glycosides are divided into 2 types based on the chemical structure of their aglycones (sapogenins). Saponins on hydrolysis yield an aglycone known as "sapogenin".

The so-called NEUTRAL saponins are derivatives of STEROIDS with spiroketal side chains. The ACID saponins possess triterpenoid structures.

The main pathway leading to both types of sapogenins is similar and involves the head-to-tail coupling of acetate units. However, a branch occurs, after the formation of the triterpenoid hydrocarbon, squalene, that leads to steroids in one direction and to cyclic triterpenoids in the other.

Sapogenins

They form the aglycon part of saponins which have well known detergent properties. They are oxygenated C27 steroids with an hydroxyl group in C-3. The structure of diosgenin is given below as an example of these compounds.                                                                            

These steroids can mimic or regulate steroid hormones. Thus, diosgenin can be chemically converted into corticosteroids, estrogens and progesterone. They are externally distributed in plants. They are extremely distributed in plants since they occur in over 90 plant families. They are used in nutrition, as herbal medicine, and in cosmetics.

Cardiac Glycosides

        Heart diseases can be primarily grouped into three major disorders:

cardiac failure, ischemia and cardiac arrhythmia.

Cardiac failure can be described as the inability of the heart to pump blood effectively at

a rate that meets the needs of the metabolizing tissues. This occurs when the muscles

that perform contraction and force the blood out of heart are performing weakly. Thus

cardiac failures primarily arise from the reduced contractility of heart muscles, especially

the ventricles. Reduced contraction of heart leads to reduced heart output but new blood

keeps coming in resulting in the increase in heart blood volume. The heart feels

congested. Hence the term congestive heart failure.

        Congested heart leads to lowered blood pressure and poor renal blood flow. This

results in the development of edema in the lower extremities and the lung (pulmonary

edema) as well as renal failure.

Cardiac Glycosides        Increasing the force of contraction of the heart (positive inotropic activity) is very important for most heart failure patients. There are several mechanisms by which this could be achieved. Cardiac steroids are perhaps the most useful.

        The cardiac glycosides are an important class of naturally occurring drugs whose actions include both beneficial and toxic effects on the heart.

Plants containing cardiac steroids have been used as poisons and heart drugs at least since 1500 B.C. Throughout history these plants or their extracts have

been variously used as arrow poisons, emetics, diuretics, and heart tonics. Cardiac steroids are widely used in the modern treatment of congestive heart

failure and for treatment of atrial fibrillation and flutter. Yet their toxicity remains a serious problem.

Structure        Cardiac glycosides are composed of two structural features : the sugar (glycoside) and the non-sugar (aglycone - steroid) moieties.                                                                                                           

The R group at the 17-position defines the class of cardiac glycoside. Two

classes have been observed in Nature - the cardenolides and the

bufadienolides.

The cardenolides have an unsaturated butyrolactone ring while the

bufadienolides have an a-pyrone ring.                                                                                          

The cardiac glycosides occur mainly in plants from which the names have been

derived. Digitalis purpurea, Digitalis lanata, Strophanthus grtus, and

Strophanthus kombe are the major sources of the cardiac glycosides.

The name digitoxin refers to a agent

consisting of digitoxigenin (aglycone) and 

sugar moieties (three).

The aglycone portion of cardiac glycosides

is more important than the glycone portion.

The aglycone moiety: The steroid nucleus has a unique set of fused ring system that makes the aglycone moiety structurally distinct from the other more common steroid ring systems. Rings A/B and C/D are cis fused while rings B/C are trans fused. Such ring fusion give the aglycone nucleus of cardiac glycosides the characteristic U shape.

The steroid nucleus has hydroxyls at 3- and 14- positions of which the sugar attachment uses the 3-OH group. 14-OH is normally unsubstituted. Many genins have OH groups at 12- and 16- positions. These additional hydroxyl groups influence the partitioning of the cardiac glycosides into the aqueous media and greatly affect the duration of action.        The lactone moiety at C-17 position is an important structural feature. The size and degree of unsaturation varies with the source of the glycoside. Normally plant sources provide a 5-membered unsaturated lactone while animal sources give a 6-membered unsaturated lactone.

Sugar moiety : 1 to 4 sugars are found to be present in most cardiac glycosides

attached to the 3β-OH group. The sugars most commonly used include L-

rhamnose, D-glucose, D-digitoxose, D-digitalose, D-digginose, D-sarmentose, L-

vallarose, and D-fructose. These sugars predominantly exist in the cardiac

glycosides in the β-conformation. The presence of acetyl group on the sugar

affects the lipophilic character and the kinetics of the entire glycoside.  Because

the order of sugars appears to have little to do with biological activity Nature has

synthesized a repertoire of numerous cardiac glycosides with differing sugar

skeleton but relatively few aglycone structures.

Cardenolides

Their structure is closely related to bufadienolides but these C23 steroids possess a butenolide ring located at C-17. The structure of digitoxigenin is given below as a typical example of cardenolides.

They are widely distributed in plants mainly as glycosides and are either toxic or

insect deterrents. As potent cardiotonics, these steroids were largely studied.

Monarch butterfly is well known to be highly toxic to birds because of

cardenolides which come from the milkweed leaves eaten by its caterpillar.

•Cardenolides (most prevalent) are C23 steroids.

                                   •Cardenolides have a hormonal nature as substances. Their effects are on the heart and

kidney. •Strong, bitter and disagreeable taste. •Cardiotonic = affect contractions of the heart muscle. •Break down in fermentation by enzymatic action. •Symptoms of poisoning include dizziness, vomiting, irregular heart beat, and delerium or

halucinations.

Treatment: atropine and activated charcoal, lidocaine •Assumed mechanism of action: inhibition of the Na+, K+-ATPase resulting in increased

intracellular sodium and subsequent intracellular calcium leading to enhanced muscle

contraction in cardiac tissue.

Cardenolides are classified according to the chemical composition of their aglycones as

lanataglucosides A, B, C, D and E.

Only Digitalis lanata, the woolly foxglove contains all five forms. The entire foxglove plant is

toxic. Digitonin is probably the best known derivative of the Digitalis cardenolides. It is a drug

derived from D. purpurea. It is used in modern medicine to increase the force of the systolic

contractions and prolong duration of the diastolic phase in congestive heart failure.

Digitalis drugs lower venous pressure in hypersensetive heart ailments, elevate blood

pressure in a weak heart act as a diuretic, and reduce edema.

However, the therapeutic dose is dangerously close to the lethal dose

Bufadienolides

They are typically polyhydroxy C24 steroids with a pentadienolide ring at C-

17. The structure of hellebrigenin is given below as a typical example of

bufadienolides.                                                                            

They have been isolated from plants and animals. More than 250 compounds

have been identified. In plants, thay are mostly glycosides with one to three

sugars in a chain linked to the 3-hydroxyl group.

They are important for their cardiotonic activity. Furthermore, they possess

insecticidal and antimicrobial properties, those produced by the toad skin are

strongly poisonous.

Structure - Activity Relationships        The sugar moiety appears to be important only for the partitioning and

kinetics of action. It possesses no biological activity. For example, elimination of the aglycone moiety eliminates the activity of

alleviating symptoms associated with cardiac failure.        

The "backbone" U shape of the steroid nucleus appears to be very important. Structures with C/D trans fusion are inactive.

        Conversion to A/B trans system leads to a marked drop in activity. Thus although not mandatory A/B cis fusion is important.

        The 14β-OH groups is now believed to be dispensible. A skeleton without 14β-OH group but retaining the C/D cis ring fusion was found to retain activity.         Lactones alone, when not attached to the steroid skeleton, are not active.

Thus the activity rests in the steroid skeleton.         The unsaturated 17-lactone plays an important role in receptor binding.

Saturation of the lactone ring dramatically reduced the biological activity.         The lactone ring is not absolutely required. For example, using a,b-

unsaturated nitrile (C=C-CN group) the lactone could be replaced with little or no loss in biological activity.

The larvae feed on the plant leaves for about two weeks and develop into caterpillars about 2 inches long. 

Monarch butterfly on milkweed

Danaus plexippus

Limenitis archippus